Many present systems for delivering active agents to targets are severely limited by biological, chemical and physical barriers, which are imposed by the environment through which delivery occurs, the environment of the target of delivery, or the target itself. For example, oral delivery of many biologically active agents, such as, for example, insulin, would be the route of choice if not for chemical and physicochemical barriers such as extreme pH in the stomach, powerful digestive enzymes, and gastrointestinal membranes which are impermeable to the active agent.
Much research has been devoted to developing designs of and manufacturing methods for effective oral drug delivery. For example, Fulwyler, et al., U.S. Pat. No. 4,162,282, disclose the production of uniform particles by introducing a laminar stream of a core liquid into a flowing body of an immiscible sheath liquid. The liquids, either of which may contain dispersed materials, and are expelled from a nozzle to form a liquid jet which is disturbed at a uniform periodic rate to create droplets.
U.S. Pat. No. 4,422,985 to Morishita, et al. describes an encapsulation in which a triple jet is introduced into a flow of cooling liquid to form capsules. The triple jet includes an inner jet of a material to be encapsulated, a middle coaxial jet of a capsule forming material around the inner jet, and an outer coaxial jet of a heated liquid surrounding the middle jet.
U.S. Pat. No. 4,481,157 to Morishita, et al. describes a microcapsule production device which includes an inner pipe for extruding a material to be encapsulated and a coaxial outer pipe for extruding an encapsulating material. Both materials are introduced into a flow of a coagulating agent to produce microcapsules.
Microspheres formed from mixed amino acid proteinolds (non-naturally occurring (i.e., artificial) polymers of mixed amino acids) have been described as delivery vehicles for pharmaceuticals in U.S. Pat. No. 4,925,673 to Steiner et al. These microspheres are typically prepared by a batch-type thermal condensation.
Shioya, et al., U.S. Pat. No. 5,040,960, describe a method and an apparatus for the production of encapsulated bodies in which a core fluid is ejected from a double-walled cylindrical nozzle into a reaction tank containing a solution capable of forming gel skins around the core fluid. The double walled nozzle allows the introduction of air to control the size of the droplets of the core fluid introduced into the reaction tank.
Mazer, et al., U.S. Pat. No. 5,160,742, describe prolamine/enteric coated microspheres which contain an active agent, while Mathiowitz, et al., U.S. Pat. No. 5,271,961, disclose pharmacologically active agents containing prolamine microspheres prepared by phase separation.
Encapsulation News, vol. 1, number 2, Southwest Research Institute, San Antonio, Tex. (1982), describes a method for producing encapsulated bodies using an air suspension coater. The batch-type air suspension coater utilizes a fluid bed of salt which is repeatedly cycled past a spray nozzle. The spray nozzle applies a wax coating around a cargo. Microcapsules are also prepared using a rotating centrifugal extrusion nozzle. The rotating nozzle apparatus has an inner nozzle for delivering the material to be encapsulated and an outer nozzle for delivering the shell material. The shell material is pumped through an annular space between the inner and outer nozzles and coats the material to be encapsulated following ejection from the rotating nozzle apparatus.
The manufacture of proteinold, modified amino acid, or protein microspheres presents significant challenges. These carrier materials are conventionally initially solubilized before microsphere formation. However, the solubilities of these carrier materials vary dependent upon the amino acid content of the carrier and consequent functional groups on their surfaces. These carriers also present other processing problems. Many proteinold, modified amino acid, or protein carriers are unstable, water insoluble, or soluble primarily only in volatile organic solvents. Volatile organic solvents are generally flammable, expensive, environmentally unfriendly, and consequently, commercially impractical to use.
Thus, there is a need for rapid and inexpensive methods to prepare microsphere delivery systems. It has now been discovered that microsphere delivery systems incorporating proteinolds, modified amino acids, proteins or conventional enteric coating materials can be prepared rapidly and economically by modified spray drying techniques.
Therefore, an object of the present invention is to provide methods for producing stable microspheres, and preferably microcapsules, for the delivery of active agents and particularly for the oral delivery of biologically active agents. Another object of the present invention is to provide an apparatus for economically producing these microspheres by spray drying.